The somatomedins are polypeptide hormones which stimulate the replication of many normal and transformed cell types. Two somatomedins have been identified in humans: insulin-like growth factors I and II (IGF-I and IGF-II). The objectives of the studies described in this proposal are to characterize the mechanism by which these hormones elicit their mitogenic effect and to asses their role in stimulating human tumor growth in vivo. Both of the IGFs stimulate replication by binding to the same cell surface receptor, the type I IGF receptor, but the mechanism by which this binding initiates the replicative response is not understood. Other growth factors stimulate the internalization of their receptors and it has been postulated that the internalized receptors catalyze the tyrosine-specific phosphorylation of key intracellular proteins and, by binding to the nucleus, regulate the expression of specific genes. The first aim of these studies is to investigate the metabolism of the type I IGF receptor in human cells: the internalization, degradation and recycling of this receptor will be examined, the tyrosine-kinase activity of the internalized receptor will be characterized, and nuclear translocation of the receptor will be investigated. The second aim of these studies is to identify the intracellular substrates of the internalized receptor tyrosine-kinase and to characterize the effects of the IGFs on the transcription of specific genes and the synthesis of selective proteins. A number of alterations in the IGF-receptor pathway could result in a loss of normal growth control and contribute to the abnormal growth of transformed cells. The third aim of these studies is to identify specific alterations in the IGF-receptor pathway occurring in transformed human cells in vitro and to determine if these alterations are characteristic of particular tumor cell types. The final aim is to determine if these alterations are important in stimulating tumor growth in vivo. To study this transformed human cell lines will be grown as tumors in nude mice and the effects of altering tissue IGF levels and of inhibiting IGF receptor function on tumor growth will be investigated. The information gained from these studies should lead to a better understanding of the mechanisms by which the IGFs regulate cell division and of how this regulation is modified in cancer cells. Such information may be valuable for designing new approaches for diagnosing and treating specific human cancers.